CN104496923B - Oil of mirbane diene tetrazole compound, Preparation Method And The Use - Google Patents
Oil of mirbane diene tetrazole compound, Preparation Method And The Use Download PDFInfo
- Publication number
- CN104496923B CN104496923B CN201510016258.5A CN201510016258A CN104496923B CN 104496923 B CN104496923 B CN 104496923B CN 201510016258 A CN201510016258 A CN 201510016258A CN 104496923 B CN104496923 B CN 104496923B
- Authority
- CN
- China
- Prior art keywords
- compound
- present
- preparation
- formula
- mirbane
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D257/00—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms
- C07D257/02—Heterocyclic compounds containing rings having four nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D257/04—Five-membered rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to the pharmaceutical field relevant to thrombotic diseases.Specifically, the present invention relates to PAR-1 antagonist, the Preparation Method And The Use of a class nitrobenzene-containing diene tetrazole structure.
wherein, R
1be selected from H, C
1-C
3alkyl, C
3-C
5cycloalkyl.
Description
Technical field
The present invention relates to the pharmaceutical field relevant to thrombus disease.Specifically, the present invention relates to PAR-1 antagonist of the medicative class nitrobenzene-containing diene tetrazole structure of thrombotic diseases and preparation method thereof, containing their pharmaceutical composition and the purposes on treatment thrombotic diseases.
Background technology
Proteinase activated receptors 1 (ProteaseActivatedAcceptor-1, PAR-1) is the novel targets of the antiplatelet class antithrombotic reagent found recently.Proteinase activated receptors 1 is thrombin receptor again, zymoplasm by coagulation cascade activate after by PAR-1 receptor acting in thrombocyte thus activate thrombocyte, cause platelet aggregation thus cause thrombus and blood coagulation.Being rich in platelet component in the thrombus that PAR-1 causes, is the main reason of arterial thrombus.PAR-1 antagonist can block thrombin activation thrombocyte, thus interruption artery thrombosis, may be used for treatment acute coronary artery disease (AcuteCoronarySyndrome).Several PAR-1 inhibitor has been had to be in clinical study (ChackalamannilS., ThrombinReceptor (ProteaseActivatedReceptor-1) AntagonistsasPotentAntithromboticAgentswithStrongAntipla teletEffects, J.Med.Chem., 2006,49 (18), 5389-5403).
Traditional is divided three classes for the medicine preventing and treating thrombotic diseases.The first kind is anticoagulation class, be divided into direct thrombin inhibitor and indirect thrombin inhibitors, such medicine carrys out inhibition thrombosis by the different links acting on coagulation cascade, has and suppresses various thrombotic effect, as vitamin K antagon and Xa factor inhibitor etc.; Equations of The Second Kind is antiplatelet class, and as COX-1 inhibitor and adp receptor antagonist etc., such medicine is mainly used in preventing and treating arterial thrombus; 3rd class is fibrinolytic agent, is mainly used in the scleroproein formed in lysed blood.
Mostly antiplatelet drug is traditional arterial thrombus protective agents, as clopidogrel and acetylsalicylic acid etc.The shortcoming of these medicines is that bleeding risk is larger.And as the PAR-1 antagonist of newfound antiplatelet class antithrombotic reagent, then there is less bleeding risk, therefore this compounds can as the very promising medicine for the treatment of arterial thrombus.
The invention discloses the PAR-1 antagonist of a class nitrobenzene-containing diene tetrazole structure, they may be used for the medicine preparing anti-arterial thrombus disease.
Summary of the invention
An object of the present invention is to provide a kind of there is good anti-thrombosis activity the compound with general formula I and pharmaceutically acceptable salt.
Another object of the present invention is to provide preparation and has the compound of general formula I and the method for pharmaceutically acceptable salt thereof.
Another object of the present invention be to provide compound containing general formula I and pharmaceutically acceptable salt as effective constituent, and the medicinal compositions of one or more pharmaceutically acceptable carrier, vehicle or thinners, and the application in treatment arterial thrombus.
Now in conjunction with object of the present invention, content of the present invention is specifically described.
The compound that the present invention has general formula I has following structural formula:
Wherein, R
1be selected from H, C
1-C
3alkyl, C
3-C
5cycloalkyl.
The preferably following compound with general formula I,
Compound of Formula I of the present invention is synthesized by the following method:
Compound II per reference literature method synthesis (CN200780022348.9), Compound II per uses LiBH
4be reduced to III; Compound III uses halide reagent to be converted into IV; IV and V is obtained by reacting I in the presence of base; Wherein said halide reagent is selected from SOCl
2, PCl
3, PCl
5, PBr
3deng, X is selected from Cl and Br.; Wherein R
1definition as previously shown.
The pharmacy acceptable salt of formula I of the present invention, include, but are not limited to the salt formed with various mineral acid example hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, Hydrogen bromide etc., also comprise the salt formed as acetic acid, succsinic acid, toxilic acid, oxysuccinic acid and each seed amino acid etc. with various organic acid.
Compound of Formula I of the present invention has the antagonistic action of PAR-1, can be used as the medicine of effective constituent for the preparation of antithrombotic aspect.The activity of compound of Formula I of the present invention is verified by external model.
Compound of Formula I of the present invention is effective in quite wide dosage range.The dosage that such as every day takes, within the scope of 1mg-500mg/ people, is divided into once or administration for several times.The actual dosage taking compound of Formula I of the present invention can be decided according to relevant situation by doctor.These situations comprise: the physical state of patient, route of administration, age, body weight, individual reaction to medicine, the severity etc. of symptom.
Embodiment
Below in conjunction with embodiment, the present invention is further illustrated.It should be noted that, following embodiment be only for illustration of, and not for limiting the present invention.The various changes that those skilled in the art's training centre according to the present invention is made all should within the protection domain required by the application's claim.
Embodiment 1
Get a 100mL round-bottomed flask, add 2.47g (10mmol) Compound II per, dissolve with the THF of 20mL drying, ice-water bath cooling is lower stirs, and adds 0.44g (20mmol) LiBH in batches
4after, continue at room temperature to stir to spend the night.TLC shows reaction to be completed.Reaction mixture pours in frozen water, stirs, regulates pH=3 with concentrated hydrochloric acid, with the dichloromethane extraction of 50mL × 3, merge extracted organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, boil off solvent on a rotary evaporator, the resistates column chromatography purification obtained, obtains product III, white solid, ESI-MS, m/z=206 ([M+H]
+).
Get the round-bottomed flask of a 100mL, add 1.64g (8mmol) compound III and 10mL methylene dichloride, ice-water bath cooling is lower stirs, and slowly adds 5.41g (20mmol) PPBr
3.After adding, reaction mixture stirred at ambient temperature 1 hour, TLC shows reaction to be completed.Reaction mixture pours in frozen water, stir, with the dichloromethane extraction of 50mL × 3, merge extracted organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, boils off solvent on a rotary evaporator, the resistates column chromatography purification obtained, obtain product IV, white solid, ESI-MS, m/z=266,268 ([M+H]
+).
Get the round-bottomed flask of a 50mL, add compound 1.34g (5mmol) IV and 0.87g (5mmol) compound V-1, dissolve with the DMF of 10mL drying, stir, then add 2.07g (15mmol) K
2cO
3, be then warming up to 100 DEG C, N
2stirred under argon spends the night.TLC shows reaction to be completed.Reaction mixture pours in frozen water, stir, with the dichloromethane extraction of 50mL × 3, merge extracted organic phase, use saturated common salt water washing, anhydrous sodium sulfate drying, boils off solvent on a rotary evaporator, the resistates column chromatography purification obtained, obtain product I-1, white solid, ESI-MS, m/z=362 ([M+H]
+).
Embodiment 2-8
According to the method for embodiment 1, synthesize the following compounds with general formula I.
Embodiment 9 extracorporeal platelet aggregation inhibition test
In 96 orifice plates, the platelet aggregation of inducing at TRAP (Glycoprotein) concentrates the pharmacology test carrying out material.The sodium citrate solution of 3.13% is added in advance in syringe, then the blood of suction 20mL healthy volunteer, under 1500g centrifugal 20 minutes, separate being rich in hematoblastic blood plasma (PRP) and processing with the amount of 1 μ LPGE1 solution (ethanolic solns of 500 μ g/mL)/mLPRP.After at room temperature hatching 5 minutes, by its under 1200g centrifugal 20 minutes with except leucocyte-removing.To not transfer in the PP pipe of 15mL with 5mL/ part containing leukocytic PRP in batches, and centrifugally under 3600g make pellet platelets.Then, drain upper plasma, the pellet platelets deriving from 5mLPRP is suspended in 1mLTyrode (120mMNaCl, 2.6mMKCl, 12mMNaHCO again
3, 0.39mMNaH
2pO
4, 10mMHEPES, 0.35%BSA, 5.5mM glucose, pH=7.4) in, and the platelet count of 3 × 105/ μ L is adjusted to Tyrode.By the 10mMCaCl of this for 13mL cell suspension with 866 μ L
2solution-treated, is drawn in 96 orifice plates with the amount of every hole 120 μ L, in the hole of 96 orifice plates, added 15 μ L material to be tested in advance.At room temperature hatch 30 minutes in dark, add 15 μ LTRAP solution (70-100 μM) as agonist, vibrate 20 minutes at 37 DEG C in SpectraMax, kinetics is noted down under 650nm, calculate the area under curve of negative control (tyrode/DMSO) and positive control (15 μ L agonist/DMSO), and difference is decided to be 100%.Aspirated with the form of serial dilution thing by compound to be tested, measure in duplicate, the same AUC measuring each material concentration, the AUC calculated compared with the control suppresses %.IC is calculated according to 4 parametric equations by nonlinear regression analysis by this suppression %
50value.Following table gives result.
| Compound | The suppression IC of platelet aggregation 50(μM) |
| I-1 | 0.49 |
| I-2 | 1.50 |
| I-3 | 0.74 |
| I-4 | 0.91 |
| I-5 | 0.53 |
| I-6 | 1.08 |
| I-7 | 1.96 |
| I-8 | 1.75 |
As can be seen from the above table, compound of the present invention all shows good restraining effect in platelet aggregation test.
Claims (4)
1. there is compound and the pharmaceutically acceptable salt thereof of general formula I,
Wherein, R
1be selected from H, C
1-C
3alkyl, C
3-C
5cycloalkyl.
2. the compound of Formula I that defines of claim 1, is selected from following compounds,
3. synthesize the method for the compound of arbitrary the defined general formula I of claim 1-2:
Compound II per uses LiBH
4be reduced to III; Compound III uses halide reagent to be converted into IV; IV and V is obtained by reacting I in the presence of base; Wherein X is selected from Cl and Br; R
1definition as arbitrary in claim 1-2 shown in.
4. the compound of Formula I that defines of any one of claim 1-2 and the pharmaceutically application of acceptable salt in preparation treatment thrombotic medicine thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510016258.5A CN104496923B (en) | 2015-01-13 | 2015-01-13 | Oil of mirbane diene tetrazole compound, Preparation Method And The Use |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510016258.5A CN104496923B (en) | 2015-01-13 | 2015-01-13 | Oil of mirbane diene tetrazole compound, Preparation Method And The Use |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104496923A CN104496923A (en) | 2015-04-08 |
| CN104496923B true CN104496923B (en) | 2016-04-06 |
Family
ID=52938397
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510016258.5A Active CN104496923B (en) | 2015-01-13 | 2015-01-13 | Oil of mirbane diene tetrazole compound, Preparation Method And The Use |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104496923B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101508712A (en) * | 2009-03-30 | 2009-08-19 | 天津药物研究院 | Glucoside containing tetrazole structure, preparation method and application |
| CN104072434B (en) * | 2014-07-23 | 2015-12-02 | 张远强 | Between position replace tetrazole acetophenone compound, Preparation Method And The Use |
-
2015
- 2015-01-13 CN CN201510016258.5A patent/CN104496923B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN104496923A (en) | 2015-04-08 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104529927B (en) | One class is containing oxadiazoles sulfoxide compound, the Preparation Method And The Use of halogeno-benzene | |
| CN104086503B (en) | PAR-1 antagonist and uses thereof | |
| CN104086500B (en) | A kind of PAR-1 antagonist and uses thereof | |
| CN104496923B (en) | Oil of mirbane diene tetrazole compound, Preparation Method And The Use | |
| CN104496925B (en) | Diene tetrazole compound, Preparation Method And The Use | |
| CN104496927B (en) | Diene tetrazole halobenzene compounds, Preparation Method And The Use | |
| CN104496924B (en) | Halobenzene diene tetrazole compound, Preparation Method And The Use | |
| CN104478819B (en) | Diene tetrazole amino benzenes compounds, Preparation Method And The Use | |
| CN104496922B (en) | Itrile group benzene diene tetrazole compound, Preparation Method And The Use | |
| CN104529923B (en) | Diene tetrazole nitrobenzene compounds, Preparation Method And The Use | |
| CN104496926B (en) | One class contains compound, the Preparation Method And The Use of diene tetrazole structure | |
| CN104513212B (en) | Oxadiazoles sulfoxide compound, the Preparation Method And The Use of one class nitrobenzene-containing | |
| CN104529930B (en) | One class nitrile group-containing Ben oxadiazole sulfoxide compound, Preparation Method And The Use | |
| CN104529931B (en) | One class is containing oxadiazoles sulfoxide compound, the Preparation Method And The Use of alcoxyl para-orientation benzene | |
| CN104529929B (en) | Containing oxadiazoles sulfoxide compound, the Preparation Method And The Use of alcoxyl substituted benzene | |
| CN104610184A (en) | Benzo diene tetrazole compound, preparation method and application of benzo diene tetrazole compound | |
| CN104356094B (en) | Trans cvclohexvl alkyl amide compound, its preparation method and in purposes pharmaceutically | |
| CN104478782B (en) | One class contains compound and the purposes of alkoxyphenyl radical and diene fluoroadamantane structure | |
| CN104356059A (en) | Halogenated pyridyl containing trans-cyclohexane amide compound and application thereof | |
| CN104356093A (en) | Halogenated phenyl-containing trans-cyclohexane amide compound and application thereof | |
| CN104356058A (en) | Alkoxypyridyl-containing trans-cyclohexane amide compound and application thereof | |
| CN104478781A (en) | Diene adamantane compound and preparation method and usage thereof | |
| CN104356095A (en) | Alkoxy phenyl substituted trans-cyclohexane amide compound and application thereof | |
| CN104529928A (en) | One category of oxadiazole sulfoxide compounds, and preparation method and application thereof | |
| CN104557656A (en) | Compound containing halobenzene and diene adamantane structure as well as preparation method and application of compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: PAR-1 antagonist containing nitrobenzene diene tetrazolium, preparation method thereof and application thereof Effective date of registration: 20170816 Granted publication date: 20160406 Pledgee: Guangdong Nanhai Rural Commercial Bank branch branch of Limited by Share Ltd Pledgor: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY CO., LTD. Registration number: 2017990000756 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20190604 Granted publication date: 20160406 Pledgee: Guangdong Nanhai Rural Commercial Bank branch branch of Limited by Share Ltd Pledgor: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY CO., LTD. Registration number: 2017990000756 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20191014 Address after: 244000 Fengxin Group 7, Charencun, Tongling Development Zone, Tongling City, Anhui Province Patentee after: Tongling Mdt InfoTech Ltd Address before: Chancheng district has 528000 Taiwan public in Guangdong province Foshan City No. 32 first floor 1636, shop No. 1637 Patentee before: FOSHAN SAIWEISI PHARMACEUTICAL TECHNOLOGY CO., LTD. |
|
| TR01 | Transfer of patent right |